A systematic approach identifies p53-DREAM target genes associated with blood or brain abnormalities.

p53 is a tumor suppressor, but mouse models revealed that increased p53 activity may cause bone marrow failure, likely through DREAM-mediated gene repression. Here we designed a systematic approach to identify p53-DREAM targets whose repression might contribute to abnormal hematopoiesis. We used gene ontology to analyze transcriptomic changes associated with bone marrow cell differentiation, then ChIP-seq data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM. The same approach was developed to find p53-DREAM targets associated with brain abnormalities, also observed in mice with increased p53 activity. Putative DREAM binding sites were found for 151 candidate target genes, of which 106 are mutated in a blood or brain genetic disorder. Twenty-one DREAM binding sites were tested and found to impact gene expression in luciferase assays, notably regulating genes mutated in dyskeratosis congenita (Rtel1), Fanconi anemia (Fanca), Diamond-Blackfan anemia (Tsr2), primary microcephaly (Casc5, Ncaph, Wdr62) or pontocerebellar hypoplasia (Toe1). These results provide clues on the role of the p53-DREAM pathway in regulating hematopoiesis and brain development, with implications for tumorigenesis.